DNA is wrapped around histone complexes termed nucleosomes and gene accessibility is determined largely by the local chromatin configuration (Chase, A. et. al. Clin. Cancer Res. 17, 2613-2618, 2011). Local chromatin structure is influenced, in part, by covalent modifications to histone tails including histone methylation. Histone methyltransferases (HMTs), a class of enzymatic “writers” of epigenetic marks, have recently emerged as targets of potential therapeutic value. They catalyze the methylation of histone lysines and arginines utilizing S-adenosyl-methionine (SAM) as the cofactor/methyl-source. This process can result in either the activation or repression of transcription. Dysregulation of methylation at specific histone sites (alterations in the “histone code”) has been implicated in many cancers (Chi P. et al. Nat. Rev. Cancer 10, 457-469, 2010). Hence, targeting HMT activity has been the subject of much investigation in the field of oncology.
More specifically, trimethylation of histone H3 lysine 27 (H3K27me3), catalyzed by the PcG (polycomb group) enhancer of zeste homolog 2 (EZH2), is associated with transcriptional repression. H3K27 methylation is catalyzed by the SET domain of EZH2 and requires the presence of additional proteins including embryonic ectoderm development (EED) as part of a larger protein complex known as polycomb repressive complex 2 (PRC2) (Bracken, A. et. al. Curr. Opin. Cell Biol. 37, 42-48, 2015).
EED functions to localize the PRC2 complex to trimethylated histone marks which propagates the repressive trimethyl mark to neighboring nucleosomes (Chinnaiyan, A. et. al. Nat. Commun. 5, 3127, 2014). Overexpression of EZH2, and in turn EED, is a marker of advanced and metastatic disease in many solid tumors including prostate (Varambally, S. et. al. Nature 419, 624-629, 2002), breast (Kleer, C. G. et. al. Proc. Natl. Acad. Sci. USA 100, 11606-11611, 2003) and esophageal cancer (He, L. et. al. Int. J. Cancer 127, 138-147, 2010). An EZH2 mutation that is linked to subsets of human B-cell lymphoma has been shown to enhance the catalytic efficiency of histone H3K27 trimethylation (Sneeringer, C. J. et. al. Proc. Natl. Acad. Sci. 107, 20980-20985, 2010). Increasing evidence suggests that repression of histone trimethylation through inhibition of the PRC2 complex has potential to treat human cancer (Orkin, S. H. Nat. Chem. Biol. 9, 643-650, 2013; Yin, J. et. al. Proc. Natl. Acad. Sci. USA 2015; Jin, P. Anticancer Agents Med. Chem. 2015; Curry, E. et. al. Clin. Epigenetics 7, 84, 2015; Xu, B. et. al. Exp. Hematol. 43, 698-712, 2015; Campbell, J. E. et. al. ACS Med. Chem. Lett. 6, 1031-1043, 2015; Verma, S. K. Curr. Top. Med. Chem. 15, 714-719, 2015; Katona, B. W. et. al. Cancer Biol. Ther. 15, 1677-1687, 2014; Mayr, C. et. al. Expert Opin. Ther. Targets 19, 363-375, 2015; Zhang, L. Oncotarget. 5, 10665-10677, 2014; Liu, T. P et. al. Anticancer Drugs 26, 139-147, 2015; Kondo, Y. J. Biochem. 156, 249-257, 2014; McCabe, M. T. Epigenomics 6, 341-351, 2014; Campbell, R. M. J. Clin. Invest. 124, 64-69, 2014).
Inhibitors of EED have the potential to suppress PRC2-dependent cancer cell growth. Thus, small molecule inhibitors of EED could be beneficial for therapeutic intervention in cancer and other PRC2-dependent disorders.